Neuropharmacological targets for drug action in vestibular sensory pathways

The use of pharmacological agents is often the preferred approach to the management of vestibular dysfunction. In the vestibular sensory pathways, the sensory neuroepithelia are thought to be influenced by a diverse number of neuroactive substances that may act to enhance or inhibit the effect of the primary neurotransmitters [i.e., glutamate (Glu) and acetylcholine (ACh)] or alter their patterns of release. This review summarizes various efforts to identify drug targets including neurotransmitter and neuromodulator receptors in the vestibular sensory pathways. Identifying these receptor targets provides a strategic basis to use specific pharmacological tools to modify receptor function in the treatment and management of debilitating balance disorders. A review of the literature reveals that most investigations of the neuropharmacology of peripheral vestibular function have been performed using in vitro or ex vivo animal preparations rather than studying drug action on the normal intact vestibular system in situ. Such noninvasive approaches could aid the development of more accurate and effective intervention strategies for the treatment of dizziness and vertigo. The current review explores the major neuropharmacological targets for drug action in the vestibular system

The Auditory Nerve Overlapped Waveform (ANOW) detects small endolymphatic manipulations that may go undetected by conventional measurements

Electrocochleography (ECochG) has been used to assess Ménière's disease, a pathology associated with endolymphatic hydrops and low-frequency sensorineural hearing loss. However, the current ECochG techniques are limited for use at high-frequencies only (≥1 kHz) and cannot be used to assess and understand the low-frequency sensorineural hearing loss in ears with Ménière's disease. In the current study, we use a relatively new ECochG technique to make measurements that originate from afferent auditory nerve fibers in the apical half of the cochlear spiral to assess effects of endolymphatic hydrops in guinea pig ears. These measurements are made from the Auditory Nerve Overlapped Waveform (ANOW). Hydrops was induced with artificial endolymph injections, iontophoretically applied Ca2+ to endolymph, and exposure to 200 Hz tones. The manipulations used in this study were far smaller than those used in previous investigations on hydrops. In response to all hydropic manipulations, ANOW amplitude to moderate level stimuli was markedly reduced but conventional ECochG measurements of compound action potential thresholds were unaffected (i.e., a less than 2 dB threshold shift). Given the origin of the ANOW, changes in ANOW amplitude likely reflect acute volume disturbances accumulate in the distensible cochlear apex. These results suggest that the ANOW could be used to advance our ability to identify initial stages of dysfunction in ears with Ménière's disease before the pathology progresses to an extent that can be detected with conventional measures

Reducing auditory nerve excitability by acute antagonism of Ca2+-permeable AMPA receptors

Hearing depends on glutamatergic synaptic transmission mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). AMPARs are tetramers, where inclusion of the GluA2 subunit reduces overall channel conductance and C

Effects of pharmacological agents on mammalian vestibular function

Three studies were largely conducted to evaluate physiological status of animals anesthetized with different anesthetic protocols and pharmacological effects on vestibular function using vestibular sensory evoked potentials (VsEP) in the intact mice. In the first study, the physiological status of mice anesthetized with ketamine/xylazine (K/X) was compared to those with urethane/xylazine (U/X) anesthesia during VsEP testing conditions. The U/X anesthesia provided a longer lasting anesthesia, prolonged survival times and less compromised physiological conditions compared to K/X anesthesia in mice. Simple non-invasive O2 supplementation and brain temperature control improved the physiological conditions and minimized changes in VsEP responses. In the second study, clinical agents (e.g., meclizine and diazepam) and a potential clinical agent (e.g., JNJ7777120) were tested to identify a useful dose range and characterize time course and extent of drug actions on vestibular function. Effects on peripheral and central components of the VsEP were modest in all three drugs and were relatively slow to develop in meclizine and JNJ7777120. Meclizine and diazepam act centrally to exert their suppression effects, whereas JNJ7777120 acts in the periphery by enhancing macular responses to transient high frequency stimuli. In the third study, a non-clinical agent (e.g., XE-991, KCNQ channel blocker) was tested to better understand the normal function of KCNQ channels and their importance to vestibular function in the intact animals. XE-991 modestly produced a dose-dependent enhancement of VsEP at doses of 0.5 mg/kg and higher and also showed a dose-dependent suppression at doses of 2.5 mg/kg and higher. The findings suggest that KCNQ channels play a critical role in vestibular function and their regulation by efferent action via muscarinic acetylcholine receptors (mAChRs) may function to adjust the dynamic response characteristics of vestibular afferents. Collectively, these studies showed that using pharmacological agents and VsEP is beneficial to resolve the questions related to vestibular afferent and efferent synaptic mechanisms. These in vivo studies determined sites of and time course of drug action in the intact vestibular system. Clinically, the findings of this work may aid the development of more accurate and effective intervention strategies for the treatment of dizziness and vertigo

The mammalian efferent vestibular system utilizes cholinergic mechanisms to excite primary vestibular afferents

Abstract Electrical stimulation of the mammalian efferent vestibular system (EVS) predominantly excites primary vestibular afferents along two distinct time scales. Although roles for acetylcholine (ACh) have been demonstrated in other vertebrates, synaptic mechanisms underlying mammalian EVS actions are not well-characterized. To determine if activation of ACh receptors account for efferent-mediated afferent excitation in mammals, we recorded afferent activity from the superior vestibular nerve of anesthetized C57BL/6 mice while stimulating EVS neurons in the brainstem, before and after administration of cholinergic antagonists. Using a normalized coefficient of variation (CV*), we broadly classified vestibular afferents as regularly- (CV*  0.1) and characterized their responses to midline or ipsilateral EVS stimulation. Afferent responses to efferent stimulation were predominantly excitatory, grew in amplitude with increasing CV*, and consisted of fast and slow components that could be identified by differences in rise time and post-stimulus duration. Both efferent-mediated excitatory components were larger in irregular afferents with ipsilateral EVS stimulation. Our pharmacological data show, for the first time in mammals, that muscarinic AChR antagonists block efferent-mediated slow excitation whereas the nicotinic AChR antagonist DHβE selectively blocks efferent-mediated fast excitation, while leaving the efferent-mediated slow component intact. These data confirm that mammalian EVS actions are predominantly cholinergic